Tanshinones inhibit the growth of breast cancer cells through epigenetic modification of Aurora A expression and function
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Yi Gong1, Yanli Li, Hamid M Abdolmaleky
1Nutrition/Metabolism Laboratory, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
Abstract:
The objectives of this study were to evaluate the effects of tanshinones from a Chinese herb Salvia Miltiorrhiza on the growth of breast cancer cells, and to elucidate cellular and molecular mechanisms of action. Tanshinones showed the dose-dependent effect on the growth inhibition of breast cancer cells in vitro, with tanshinone I (T1) the most potent agent. T1 was also the only tanshinone to have potent activity in inhibiting the growth of the triple-negative breast cancer cell line MDA-MB231. T1 caused cell cycle arrests of both estrogen-dependent and estrogen-independent cell lines associated with alterations of cyclinD, CDK4 and cyclinB, and induced breast cancer cell apoptosis associated with upregulation of c-PARP and downregulation of survivin and Aurora A. Among these associated biomarkers, Aurora A showed the most consistent pattern with the anti-growth activity of tanshinones. Overexpression of Aurora A was also verified in breast tumors. The gene function assay showed that knockdown of Aurora A by siRNA dramatically reduced the growth-inhibition and apoptosis-induction activities of T1, suggesting Aurora A as an important functional target of T1 action. On the other hand, tanshinones had much less adverse effects on normal mammary epithelial cells. Epigenetic mechanism studies showed that overexpression of Aurora A gene in breast cancer cells was not regulated by gene promoter DNA methylation, but by histone acetylation. T1 treatment significantly reduced acetylation levels of histone H3 associated with Aurora A gene. Our results supported the potent activity of T1 in inhibiting the growth of breast cancer cells in vitro in part by downregulation of Aurora A gene function. Our previous studies also demonstrated that T1 had potent anti-angiogenesis activity and minimal side effects in vivo. Altogether, this study warrants further investigation to develop T1 as an effective and safe agent for the therapy and prevention of breast cancer.
Insights
Tanshinones from Salvia Miltiorrhiza inhibit breast cancer cell growth, particularly tanshinone I (T1). T1 targets Aurora A, a protein overexpressed in tumors, offering a potential new breast cancer therapy with minimal side effects.
Area of Science:
- Pharmacology
- Molecular Biology
- Oncology
Background:
- Breast cancer remains a leading cause of cancer-related mortality worldwide.
- Novel therapeutic agents with improved efficacy and safety profiles are urgently needed.
- Salvia Miltiorrhiza and its active compounds, tanshinones, have shown potential in traditional medicine and preliminary studies.
Purpose of the Study:
- To evaluate the anti-cancer effects of tanshinones on breast cancer cells in vitro.
- To elucidate the cellular and molecular mechanisms underlying tanshinone-induced growth inhibition and apoptosis.
- To investigate the role of Aurora A kinase as a potential therapeutic target.
Main Methods:
- In vitro cell culture of estrogen-dependent and -independent breast cancer cell lines, including triple-negative MDA-MB231.
- Dose-response assays to determine growth inhibition.
- Cell cycle analysis and apoptosis assays (Western blotting for c-PARP, survivin, Aurora A).
- siRNA-mediated knockdown of Aurora A.
- Epigenetic analysis (DNA methylation and histone acetylation assays).
Main Results:
- Tanshinones exhibited dose-dependent inhibition of breast cancer cell growth, with tanshinone I (T1) being the most potent.
- T1 effectively inhibited triple-negative breast cancer cells and induced cell cycle arrest and apoptosis.
- T1's anti-growth activity was strongly correlated with the downregulation of Aurora A, a validated target.
- T1 treatment reduced histone H3 acetylation at the Aurora A gene, suggesting epigenetic regulation.
- Tanshinones demonstrated minimal adverse effects on normal mammary epithelial cells.
Conclusions:
- Tanshinone I (T1) possesses potent in vitro activity against breast cancer cells, including triple-negative subtypes.
- Downregulation of Aurora A kinase is a key mechanism mediating T1's anti-cancer effects.
- Epigenetic modulation, specifically reduced histone acetylation, contributes to Aurora A gene regulation by T1.
- T1 represents a promising candidate for further development as a safe and effective breast cancer therapeutic agent.
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